0599728 - ÚMG 2025 RIV DE eng J - Journal Article
Stoyanov, Miroslav - Martiníková, Andra Stefania - Matějková, K. - Horáčková, K. - Zemánková, P. - Burdová, Kamila - Zemanová, Z. - Kleiblová, P. - Kleibl, Z. - Macůrek, Libor
PPM1D activity promotes cellular transformation by preventing senescence and cell death.
Oncogene. Roč. 43, č. 42 (2024), s. 3081-3093. ISSN 0950-9232. E-ISSN 1476-5594
R&D Projects: GA MZd NU22-03-00276; GA MŠMT LX22NPO5102; GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045
Institutional support: RVO:68378050
Keywords : oncogene-induced senescence * dna-damage response * cyclic gmp-amp * wip1 phosphatase * cancer * p53 * ras * inhibition * mutations * chromatin
OECD category: Cell biology
Impact factor: 6.9, year: 2023 ; AIS: 2.032, rok: 2023
Method of publishing: Open access
Result website:
https://www.nature.com/articles/s41388-024-03149-3DOI: https://doi.org/10.1038/s41388-024-03149-3

Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active RAS oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.
Permanent Link: https://hdl.handle.net/11104/0358299